Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction

Lucas Alvizi (), Diogo Nani, Luciano Abreu Brito, Gerson Shigeru Kobayashi, Maria Rita Passos-Bueno () and Roberto Mayor ()
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Lucas Alvizi: University College London
Diogo Nani: Universidade de Sao Paulo
Luciano Abreu Brito: Universidade de Sao Paulo
Gerson Shigeru Kobayashi: Universidade de Sao Paulo
Maria Rita Passos-Bueno: Universidade de Sao Paulo
Roberto Mayor: University College London

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Gene–environment interactions are believed to play a role in multifactorial phenotypes, although poorly described mechanistically. Cleft lip/palate (CLP), the most common craniofacial malformation, has been associated with both genetic and environmental factors, with little gene–environment interaction experimentally demonstrated. Here, we study CLP families harbouring CDH1/E-Cadherin variants with incomplete penetrance and we explore the association of pro-inflammatory conditions to CLP. By studying neural crest (NC) from mouse, Xenopus and humans, we show that CLP can be explained by a 2-hit model, where NC migration is impaired by a combination of genetic (CDH1 loss-of-function) and environmental (pro-inflammatory activation) factors, leading to CLP. Finally, using in vivo targeted methylation assays, we demonstrate that CDH1 hypermethylation is the major target of the pro-inflammatory response, and a direct regulator of E-cadherin levels and NC migration. These results unveil a gene–environment interaction during craniofacial development and provide a 2-hit mechanism to explain cleft lip/palate aetiology.

Date: 2023
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DOI: 10.1038/s41467-023-38526-1

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